The mode of action of clinically useful local anesthetic agents is generally believed to be on the nerve membrane. Local anesthetic agents can produce several effects on nerve membranes which lead to blocking the propagation of nerve impulses. There are numerous therapeutic agents known which produce a local anesthetic effect in mammalian systems. Generally, these therapeutic agents are categorized in two categories: (a) those which exert their local anesthetic effect by acting at receptive sites within the nerve membrane to block the sodium channels and for those which do not penetrate the membrane easily, by acting on exterior sites to block the exterior openings of the sodium; and (b) those which act through a less selective process on the membrane by exerting a physicochemical effect or a combination of effects on the nerve cell.
Tetrodotoxin, which is one of the most potent blockers of axonal conduction, is an example of a local anesthetic agent generally considered to act by blocking the exterior openings of the sodium channels. Procaine and licocaine exemplify local anesthetic agents which are believed to exert their effect by penetrating into the membrane and acting at sites deeper within the sodium channels. It is generally believed that both categories of drugs act by impairing by function of sodium transport within the channel and sufficiently to block nerve function. Aliphatic alcohols are examples of anesthetics believed to act through physicochemical effects.
Local anesthetic agents having nerve blocking effects have been differentiated between those which produce total blocking of nerve impulse conduction at any impulse frequency (Condouris et al., JADSA, Vol. VIII Number 3, March 1961; Condouris, Epilepsia, 10 (1969) pp. 224-227; Condouris, Advances in Pain Research and Therapy, Vol. 1, pp. 663-667 (1976) ) and those which produce block of a single impulse without blocking high frequency impulses (Condouris et al., The Pharmacologist, Vol. 9, No. 2-Fall, 1967; Condouris et al., Fourth International Congress on Pharmacology, Basel, Switzerland, July 14-18, 1969).
Compounds which will produce a clearly differentiated high frequency impulse block without also significantly affecting single impulse conduction at the same concentration levels are needed in order to provide a better understanding of the mechanism of nerve impulse propagation. It has now been found that certain triazinone derivatives can differentiate between a single impulse and high frequency impulses. Such agents are expected to have clinical utility in situations involving pathological disorders which are characterized by unusual prolonged high frequency discharge and compounds having such activity are useful tools for studying the initiation and propagation of nerve impulses and may be useful as aids in diagnosing and locating diseases characterized by defective nerve conduction. Effector organ response is associated with nerve impulses initiated at a local region of nerve membrane and conducted along an axon to or from the effector organ. Treatments of the type disclosed herein can be used to modify sensations dependent on high frequency impulse trains and may be used to modify conditions caused by high frequency nerve impulse conduction of propagation as an aberrant function such as the nerve impulses associated with low back pain, trigeminal neuralgia, musculo-skeletal pains, dental pain, pain associated with myofacial trigger areas, and similar disorders. Accordingly, it is an object of this invention to provide a method for treating patients suffering from pathological symptoms associated with exaggerated nerve membrane excitation and further, to provide a useful tool for the study and understanding of the propagation of nerve impulses.